Introduction

International guidelines recommend universal and immediate treatment of HIV-infected neonates, which poses a significant challenge given the lack of suitable formulations in this age group.

Three posters at CROI showed novel "sprinkle" formulations of two integrase inhibitors and a protease inhibitor.

Dolutegravir

Dolutegravir (DTG) is a promising integrase inhibitor currently in phase 3 of development. The compound is interesting for several reasons: once daily dosing for treatment naive patients, low milligram dose (50 mg, so potential for co-formulation and low cost), adequate plasma exposure without boosting, few expected drug interactions, an expected different resistance profile to raltegravir and a very comprehensive development plan. 96-week phase 3 data was also presented at CROI 2012 (see above).

The developers -- a partnership between Shionogi & Co and ViiV Healthcare -- plan to study the compound in all paediatric age groups down to young infants, a population woefully short of appropriate antiretroviral formulations. DTG is currently being studied in children 6  18 years in IMPAACT P1093.

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Parul Patel and colleagues presented findings from an evaluation of the single dose pharmacokinetics (PK) in healthy adults of a new oral granule formulation of DTG, in development for infants and young children. [1] The granules were given with and without 30 mL of various liquids and compared to the current tablet formulation given with 240 mL of tap water.

This was a single-centre, randomised, open-label, 5-way crossover study in 20 healthy adult subjects. Subjects received a single dose of DTG 50 mg as the phase 3 tablet and in 10 g of granule given: direct to mouth with no liquid; with purified water; with mineral water containing high caution concentrations (Contrex); or with infant formula milk. All formulations were administered in fasting state.

The study treatments were separated by seven days. Safety evaluations and serial PK samples were collected over 48 hours in each dosing period. The PK parameters of DTG were estimated using noncompartmental methods; geometric least squares (GLS) mean ratios and 90% CI were generated to compare treatments. Taste was assessed using a questionnaire that examined bitterness, sweetness and colour.

The investigators reported DTG exposures of the granule formulation were all moderately higher than the tablet formulation with or without liquids (55% -- 83% and 62% -- 102% for AUC 0-INF and Cmax respectively, see Table 1). Exposure was highest when the granule formulation was given with formula milk.

Inter-subject variability from the granule formulation was modest with a coefficient variation for AUC of 31-43%. DTG was well tolerated and there were no withdrawals due to AEs. The subjects rated the taste as acceptable for all treatments.

Table 1: Comparison of PK Parameters of Dolutegravir

Granule comparison to tablet

GLS mean ratio (90% CI)

AUC 0-INF

Cmax

Direct to mouth

1.58 (1.46 - 1.71)

1.62 (1.49 - 1.77)

With purified water

1.57 (1.45 - 1.69)

1.66 (1.52 - 1.81)

With mineral water

1.55 (1.43 - 1.67)

1.65 (1.51 - 1.79)

With formula milk

1.83 (1.69 - 1.98)

2.02 (1.86 - 2.20)

These data indicate that the DTG granule formulation can be given without restriction on the type of liquid or can be given alone. The taste was not considered to be a barrier to further development although the investigators noted that children's preference could be different to that of adults. The granule formulation is being studied further in children in IMPAACT P1093.

This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.

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